A schematic representation of osteoclast differentiation supported by osteoblasts/stromal cells. RANKL, which is induced by bone resorbing factors such as 1-α,25(OH)2D3, parathyroid hormone (PTH) and IL-11 on the plasma membrane of osteoblasts/stromal cells, binds its receptor RANK present in osteoclast progenitors and mature osteoclasts. Osteoprotegerin (OPG), a decoy receptor for RANKL, strongly and competitively inhibits the RANKL–RANK interaction. The RANK signaling is transduced via TNF receptor-associated factor 2 (TRAF2) and TNF receptor-associated factor 6 (TRAF6), leading to the activation of NF-κB and Jun kinase (JNK), which in turn stimulates differentiation and activation of osteoclasts. M-CSF, macrophage colony-stimulating factor.